bHLH Transcription Factors in Prostate Cancer Malignancy

前列腺癌恶性肿瘤中的 bHLH 转录因子

• 批准号: 6774725
• 负责人: CYNTHIA M SMAS
• 金额: $ 26.17万
• 依托单位: UNIVERSITY OF TOLEDO HEALTH SCI CAMPUS
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-11 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6774725
• 关键词: androgens; biological signal transduction; cell line; clinical research; gene expression; genetic regulation; human tissue; neoplastic growth; polymerase chain reaction; prostate neoplasms; protein structure function; tissue /cell culture; transcription factor; western blottings; yeast two hybrid system

DESCRIPTION (provided by applicant): Prostate cancer is the most frequently diagnosed malignancy in men and androgen ablation therapy is the main course of treatment. In many cases the disease progresses to an androgen-resistant state, for which there are few viable treatment options. Elucidation of the molecular steps of this process may identify novel points of therapeutic intervention. We have recently determined that the inhibitor of DNA binding, Id1, a member of the helix-loop-helix (HLH) family of transcriptional regulators, is downregulated in androgen-dependent, less aggressive LNCaP human prostate cells but expressed in their androgen-independent counterparts. It is also expressed in androgen-independent DU145 and PC3 cells. Moreover, Id1 is overexpressed in human prostate cancer. This supports the hypothesis that in aggressive prostate cancer cells Id1 complexes various helix-loop-helix (bHLH) binding partners to alter transcriptional activity, with an end result of promoting increased malignancy and facilitating transition to androgen independence. The proposed work addresses in detail the functional role of Id1, its E-protein binding partners, and other bHLH factors in prostate cancer malignancy with the following specific aims: 1.) The expression pattern and regulation bHLH factors, their interacting proteins and target genes in in vitro and in vivo models of prostate malignancy. 2.) By altering the levels of bHLH factors using a tetracycline-regulated expression system, the impact of these proteins on prostate cell malignancy will be determined by in vitro and in vivo assays. Overexpression of Id1 is predicted to increase malignancy while ectopic expression of E12 by alleviating the tumorigenic effects of Id1, is predicted to decrease malignancy. 3.) Pathways of Id1 and E-protein bHLH protein action in prostate will be identified by yeast two hybrid screening for Id1 and E12 binding partners and with suppressive subtractive hybridization and array-based analysis of Id1 and E-protein target genes. Id genes and bHLH factors may be suitable targets for development of new treatments for advanced prostate cancer.

描述(申请人提供)：前列腺癌是男性最常见的恶性肿瘤，雄激素消融治疗是主要的治疗过程。在许多情况下，这种疾病会进展到雄激素抵抗状态，对此几乎没有可行的治疗选择。阐明这一过程的分子步骤可能会确定新的治疗干预点。我们最近确定，DNA结合抑制因子Id1是螺旋-环-螺旋(HLH)转录调控家族的成员，在雄激素依赖、侵袭力较弱的LNCaP人前列腺细胞中表达下调，但在雄激素非依赖性前列腺细胞中表达。它也在雄激素非依赖性的DU145和PC3细胞中表达。此外，Id1在人类前列腺癌中过表达。这支持了一种假设，即在侵袭性前列腺癌细胞中，Id1与不同的螺旋-环-螺旋(BHLH)结合伙伴改变转录活性，最终结果是促进恶性增加并促进向雄激素非依赖性转变。这项拟议的工作详细阐述了Id1、其E蛋白结合伙伴和其他bHLH因子在前列腺癌恶性肿瘤中的功能作用，具体目的如下：1.Hhlh因子及其相互作用蛋白和靶基因在前列腺癌体内外模型中的表达模式和调控。2.)通过利用四环素调节的表达系统改变bHLH因子的水平，这些蛋白质对前列腺细胞恶性肿瘤的影响将通过体外和体内试验来确定。Id1的过度表达预计会增加恶性程度，而E12的异位表达通过减轻Id1的致瘤作用而预计会降低恶性程度。3.)将通过酵母双杂交筛选Id1和E12结合伙伴以及抑制消减杂交和基于阵列的Id1和E蛋白靶基因分析来确定Id1和E蛋白bHLH蛋白在前列腺中的作用途径。ID基因和bHLH因子可能是开发晚期前列腺癌新治疗方法的合适靶点。